(a) Field of the Invention
This invention relates to unsymmetrical di-(acyl)-alkanediamine useful as acetaldehyde dehydrogenase inhibitors, to intermediates therefor and to processes for their preparation.
(B) Description of the Prior Art
N,N'-Bis(dichloroacetyl)-1,8-octanediamine, also known as Win 18,466, has been shown: (a) to have antispermatogenic activity in rats [F. Coulston, A. L. Beyler and H. P. Drobeck, Tox. and Appl. Pharmacology 2, 715-731 (1960)]; (b) to suppress spermatogenesis in man [C. G. Heller, D. J. Moore and C. A. Paulsen, Tox. and Appl. Pharmacology 3, 1-11 (1961]; (c) not to have in vivo amebicidal activity against E. criceti in hamsters [D. A. Berberian R. G. Slighter and A. R. Surrey, Antibiotics and Chemotherapy 11, 245-255 (1961)]; and, (d) to be an inhibitor of aldehyde dehydrogenase [R. A. Deitrich and L. Hellerman, J. Biol. Chem. 238, No. 5, 1683-1689 (May 1963)]. In discussing Win 18,466, Deitrich and Hellerman note that through their evaluation "results in a considerable underestimation of the effectiveness" of Win 18,466 and Win 13,099 [Win 13,099 is N,N'-bis(dichloroacetyl)-N,N'-diethyl-1,4-bis(aminomethyl)benzene], "they appear to be about as effective as disulfiram", bis(diethylthiocarbamoyl) disulfide or ANTABUSE.RTM., an aid useful in treating alcoholism. Deitrich and Hellerman also report the following information about these two Win compounds: "One side effect of these compounds has been a reaction to ethanol in man and animals".
N,N'-Bis(benzoyl)-1,8-octanediamine was prepared by V. Prelog by reaction 1,8-octanediamine dihydrochloride with benzoyl chloride in aqueous potassium hydroxide solution [Helv. Chim. Acta 38, 1095 (1110) (1955)].
The SDI G. Y. Lesher U.S. Pat. No. 3,840,598, issued Oct. 8, 1974, discloses inter alia some unsymmetrical N,N'-diacyl-alkanediamines where "alkane" has from five to twelve carbon atoms, however, both "acyl" groups are 4-substituted benzoyl, at least one being 4-trifluoromethoxy(or the like)-benzoyl and the other being various 4-substituted-benzoyl groups, for example, 4-chloro-4'-trifluoromethoxy-N,N'-heptamethylenebis(benzamide). These compounds are disclosed as having antifertility activity, hypocholesteremic activity or adrenal hypertrophy activity. The intermediate N-(7-aminoheptyl)-4-(trifluoromethoxy)benzamide as its hydrochloride is prepared in Example 22 in two steps by first reacting 7-aminoheptanonitrile with 4-trifluoromethoxybenzoyl fluoride in chloroform and aqueous sodium hydroxide solution and catalytically hydrogenating in the presence of ammonia and Raney nickel the resulting N-(6-cyanohexyl)-4-trifluoromethoxybenzamide to produce said corresponding N-(7-aminoheptyl) compound.
The following N,N'-bis(3,5-dihalosalicyloyl)alkanediamines were shown to have in vitro antibacterial activity [Jerchel et al., Ann. d. Chemie 590, 242-248 (1954)]:
______________________________________ ##STR1## No. n X ______________________________________ 1 2 Cl 2 5 Cl 3 6 Cl 4 6 Br 5 8 Cl ______________________________________